RESEARCH SUMMARY Combination antiretroviral therapy (cART) has significantly increased the longevity and quality of life for people living with HIV, however, it does not target long-lived virus-infected cells, such as tissue macrophages (M)s, leaving persistent reservoirs of virus unaffected. In addition to presenting a major obstacle in virus eradication, this limitation of cART allows for the continued development and progression of HIV-related pathologies, including HIV-associated neurocognitive dysfunction (HAND). Previous work from our laboratory suggest that in HIV infection, monocyte/M homeostasis is skewed to an immunosuppressive type 2 phenotype, which supports viral persistence in Ms and invasion of infected and non-infected Ms in the brain. In the studies proposed in this application, we will explore our hypothesis that that monocyte/M homeostasis is dysregulated through chronic and/or augmented cFMS signaling in HIV infection that facilitates the establishment, expansion and maintenance of M viral reservoirs, as well as immune suppression. Through in vitro studies, we will evaluate the effect of ligands for cFMS, M-CSF and IL-34, on primary monocyte/M maturation and polarization, survival and migration, within and outside the context of HIV infection, as well as investigate differences and similarities in M-CSF and IL-34 cFMS signaling pathways. Expression of M-CSF, IL-34, cFMS, and other markers and factors associated with M activation/polarization will be investigated in banked plasma and (non-matched) postmortem brain tissue from patients with and without HIV-1 infection. We also hypothesize that targeting cFMS can be used to correct monocyte/M immune polarization and restore appropriate immune responses that will enable the immune system to clear cellular HIV reservoirs. To explore this hypothesis, we will evaluate the ability of compounds that inhibit cFMS kinase to restore monocyte/M immune homeostasis and function and promote the elimination of reservoirs of HIV infected Ms by reducing virus replication in Ms, as well as support appropriate adaptive immune responses. Candidate compounds will include those that can be advanced for investigation in the SIV rhesus macaque animal model of HIV infection. We anticipate these studies will reveal important insights into how viral persistence is achieved in tissue Ms and present a novel strategy for targeted therapeutic design to eradicate HIV-1 infection through the restoration of immune function, leading to the effective elimination of long-lived viral reservoirs.